Therapeutical methods, formulations and nutraceutical formulations

ABSTRACT

The invention provides compositions and methods for the prevention, treatment, or management of sexual dysfunction, such as premature ejaculation. The method comprises administering an effective amount of tetrahydropalmatine or its derivative or Rhizoma  Corydalis  extract containing composition to a human male on an as-needed basis shortly before sexual activity to delay ejaculation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/427,816 filed on Nov. 30, 2016, which is a Continuation-In-Partapplication of U.S. patent application Ser. No. 14/824,078 filed on Aug.12, 2015. The entire disclosure of the prior application is consideredto be part of the disclosure of the instant application and is herebyincorporated by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to methods and compositions of delayingejaculation. In particular, the invention relates to a method ofdelaying ejaculation by the administration of a tetrahydropalmatine orits derivative or Rhizoma Corydalis extract containing composition. Thecompositions can also be used to treat depression.

Background Information

Premature ejaculation is a debilitating sexual dysfunction. Thisdysfunction can lead to an inability to enter into, or sustain,relationships and can cause psychological damage to sufferers. Prematureejaculation can also impair reproductive success. Treatments forpremature ejaculation include psychological therapies, topicalanesthetics, and the use of devices. All of these treatments havesignificant drawbacks. Psychological therapies benefit only a subset ofpatients and require specialized therapists who may not be available toall patients. Furthermore, psychological therapies cannot alleviatepremature ejaculation resulting from non-psychological causes.Anesthetic agents decrease sensitivity of tissues, thereby diminishingsexual pleasure. Also, topical anesthetics can be transferred to sexualpartners and thereby decrease their sensitivity and pleasure as well.With regard to devices, these can be awkward, inconvenient andembarrassing to use. Devices are highly conspicuous and reveal the verycondition which the suffering partner may prefer to conceal.Additionally, devices can cause irritation to one or both partners.Methods for treating premature ejaculation by systemic administration offluoxetine, sertraline, Paroxetine, Dapoxetine and tramadol have beendescribed. However, these drugs may not be effective for all patients,and their side effects can halt treatment or impair patient compliance.Disease states or adverse interactions with other drugs maycontraindicate the use of these compounds or require lower dosages thatmay not be effective to delay the onset of ejaculation.

DESCRIPTION OF THE INVENTIONS AND THE PREFERRED EMBODIMENT

The current invention discloses methods, reagents and pharmaceuticalformulations to treat PE (premature ejaculation) or increase thepre-ejaculation time during sexual activity. It also discloses methods,reagents and pharmaceutical formulations to treat erectile dysfunction,cancer, and depression.

One aspect of the current invention provides a low side effect, rapidonset composition to treat premature ejaculation or increase thepre-ejaculation time during sexual activity. It also provide a method totreat premature ejaculation or increase the pre ejaculation time duringsexual activity by taking the said formulation orally within 10 hoursbefore intercourse. One example of a preferred composition contains 1˜20mg of escitalopram or 20-100 mg hyperforin, and/or 100-1000 mg RhizomaCorydalis extract and 50˜2000 mg of curcumin or curcumin salt (e.g.curcumin sodium salt) or curcumin derivative. Optionally it can furthercontains 1˜20 mg of piperine or turmeric oil. Suitable dosage formsinclude capsule, liquid capsule, tablet, lozenge, liquid gel, solution(e.g. in 50% ethanol solution) and etc.

The formulation contains one or more antidepressant selected formnatural or synthetic SNRI or SSRIs or agomelatine (Valdoxan). Thesuitable amount of drug used in the formulation is 5%˜100% dosage amountof the amount used as antidepressants. Synthetic SNRI is serotonin andnorepinephrine reuptake inhibitor, such as venlafaxine, duloxetine.SSRIs are selective serotonin reuptake inhibitors that are generallyused antidepressants. Examples of synthetic SSRIs include fluoxetine(Prozac), paroxetine (Paxil), and sertraline (Zoloft), dapoxetine,escitalopram and citalopram.

The formulation also contains curcuminoid polyphenol (curcumin typecompound). The suitable amount of curcuminoid used in the formulation isbetween 20 mg-2000 mg.

Suitable curcumin type compound can be either pure curcumin(diferuloylmethane) or curcuminoid mixture (e.g. that extracted fromturmeric, contains approximately 70˜80% diferuloylmethane, 10-20%demethoxycurcumin, and 5-10% bisdemethoxycurcumin) or curcuminderivatives. The pure curcumin (diferuloylmethane) performs similar ascurcuminoid extracted from turmeric. The terms curcumin, turmericextract and curcuminoid are used interchangeable in the currentinvention.

Optionally the composition can further contain 1˜20 mg of piperine orchavicine. Piperine, along with its isomer chavicine, is the alkaloidresponsible for the pungency of black pepper and long pepper. Optionallyturmeric oil (turmerne) can also be added to improve bioavailability ofcurcumin. One example is Biocurcumax (curcumin mixed with turmeric oil).Optionally it can further contain caffeine 20˜200 mg. Optionally it canfurther contain cGMP-specific phosphodiesterase (PDES) inhibitor. Thesuitable dose of PDES inhibitor is 20%˜150% dosage amount of the amountused in treating erectile dysfunction. Bile acid, chitin or none ionicsurfactant such as Poloxamer or Tween (e.g. tween-80) can be added tothe formulation to improve the absorption of the drug.

Example of suitable PDES inhibitor can be selected from avanafil,lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil,zaprinast and icariin. Sildenafil can be added to the formulation at theamount between 10˜100 mg. Tadalafil can be added to the formulation atthe amount between 1 mg˜20 mg. Vardenafil can be added to theformulation at the amount between 1 mg˜20 mg.

Suitable amount of antidepressant used in the formulation is Paroxetine2.5-30 mg, Sertraline 5-100 mg, escitalopram 1-20 mg, citalopram 2-40mg, dapoxetine 5-60 mg, fluoxetine 5-80 mg, Venlafaxine 5-30 mg,duloxetine 5-60 mg.

In one embodiment, a volunteer took a capsule containing 10 mg ofescitalopram, 500 mg of curcuminoid. After 3 hours, the pre ejaculationtime was 30 minutes compared with 10 minutes previously without thedrug. After 20 hours, the pre ejaculation time was 20 minutes comparedwith 10 minutes previously without the drug.

In another embodiment, a volunteer took 10 ml 50% ethanol aqueoussolution containing 10 mg Escitalopram and 500 mg of curcumin in theform of curcuminoid extract from turmeric. After 1.5 hours, the preejaculation time was 30 minutes compared with 10 minutes previouslywithout the drug. After 20 hours, the pre ejaculation time was 20minutes compared with 10 minutes previously without the drug. In anotherembodiment, a volunteer took a capsule containing 5 mg of escitalopram,300 mg of curcuminoid extract from turmeric and 2 mg of piperine. After3 hours, the pre-ejaculation time was 20 minutes compared with 5 minuteswithout the drug previously. After 20 hours, the pre-ejaculation timewas 20 minutes compared with 5 minutes previously without the drug.

In another embodiment, a volunteer took 5 ml 50% ethanol aqueoussolution containing 5 mg of escitalopram, 300 mg of curcumin and 2 mg ofpiperine. After 1.5 hours, the pre ejaculation time was 20 minutescompared with 5 minutes without the drug previously. After 20 hours, thepre ejaculation time was 20 minutes compared with 5 minutes previouslywithout the drug.

In another embodiment, a volunteer took a capsule containing 10 mg ofcitalopram, 500 mg of curcumin and 2 mg of piperine. After 3 hours, thepre ejaculation time was 20 minutes compared with 5 minutes without thedrug previously. In another embodiment, a volunteer took a capsulecontaining 1 mg of citalopram, 500 mg of curcumin and 2 mg of piperine.After 3 hours, the pre ejaculation time was 15 minutes compared with 5minutes without the drug previously. The volunteer also reportedimproved erection.

It is known that many antidepressants can reduce sex drive and furthercause erection dysfunction. The addition of curcuminoid can reduce theseside effects and further improve erection.

In another embodiment, a volunteer took a capsule containing 3 mg ofescitalopram, 200 mg of curcumin and 30 mg of sildenafil. After 2 hours,the pre ejaculation time was 20 minutes compared with 5 minutes withoutthe drug previously. The volunteer also reported improved erection.

In another embodiment, the formulation is a liquid form contains 5 ml50% ethanol, 5 mg of escitalopram, 20 mg caffeine, 250 mg of curcuminand 5 mg of vardenafil. The liquid can be taken by the person in needbefore sexual activity.

In another embodiment, the formulation is a liquid capsule contains 5 mgof escitalopram, 200 mg of curcumin and 30 mg of sildenafil in 50%glycerol, 20% ethanol solution. The capsule can be taken by the personin need 3 hours before the sexual activity.

When volunteers took 20 mg of escitalopram only once orally, significantside effects were observed (stomach irritation, nausea and headache) andno significant changes in pre ejaculation time were observed after 3hours. When same volunteers took a capsule containing 10 mg ofescitalopram+curcumin 500 mg once, much lower side effects were observedand significant increases in pre ejaculation time were observed after 3hours. When same volunteers took a capsule containing 5 mg ofescitalopram+curcumin 500 mg+2 mg of piperine once, no side effects wereobserved and significant increase in pre ejaculation time were observedafter 3 hours comparable to 10 mg of escitalopram+curcumin 500 mg. Whenthe same volunteers took a capsule containing curcumin 500 mg orcurcumin 500 mg+2 mg of piperine, no significant changes in preejaculation time were observed after 1 hours, 3 hours and 12 hours.

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 10 mg of paroxetine, 500 mg of curcumin. After 3 hours, theaverage pre ejaculation time was 25 minutes compared with 10 minutespreviously without the drug. The volunteer reported slight side effects(mild nausea).

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 5 mg of paroxetine, 500 mg of curcumin. After 3 hours, theaverage pre ejaculation time was 15 minutes compared with 10 minutespreviously without the drug. The volunteer reported very slight sideeffects (very mild nausea).

In another embodiment, in repeated experiments a volunteer took acapsule containing 5 mg of paroxetine, 300 mg of curcumin and 2 mg ofpiperine. After 3 hours, the average pre ejaculation time was 15 minutescompared with 5 minutes without the drug previously. The volunteerreported no significant side effects. In repeated experiments the samevolunteer took a capsule containing 30 mg of paroxetine only and theaverage pre ejaculation time was 8 minutes after 3 hours compared with 5minutes without the drug previously. However the volunteer reportedsignificant side effects (stomach irritation, nausea and headache).

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 20 mg of dapoxetine, 500 mg of curcumin. After 3 hours, theaverage pre ejaculation time was 20 minutes compared with 10 minutespreviously without the drug. The volunteer reported slight side effects(mild nausea).

In another embodiment, in repeated experiments a volunteer took acapsule containing 15 mg of dapoxetine, 300 mg of curcumin and 2 mg ofpiperine. After 3 hours, the average pre ejaculation time was 20 minutescompared with 5 minutes without the drug previously. The volunteerreported no significant side effects. In repeated experiments the samevolunteer took a capsule containing 60 mg of dapoxetine only and theaverage pre ejaculation time was 20 minutes after 3 hours compared with5 minutes without the drug previously. However the volunteer reportedsignificant side effects (stomach irritation, nausea and headache).

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 30 mg of sertraline, 500 mg of curcumin. After 3 hours, theaverage pre ejaculation time was 15 minutes compared with 5 minutespreviously without the drug. The volunteer reported slight side effects(mild nausea). In repeated experiments the same volunteer took a capsulecontaining 60 mg of sertraline only and no significant increase inpre-ejaculation time was observed after 3 hours; and the volunteerreported significant side effects (stomach irritation, nausea andheadache). Only after taking the 60 mg of sertraline once daily for 10days continuously, the average pre ejaculation time was 10 minutescompared with 5 minutes previously without the drug.

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 30 mg of duloxetine, 500 mg of curcumin. After 3 hours, theaverage pre ejaculation time was 10 minutes compared with 5 minutespreviously without the drug. The volunteer reported slight side effects(mild nausea). In repeated experiments the same volunteer took a capsulecontaining 60 mg of duloxetine only and no significant increase inpre-ejaculation time was observed after 3 hours; and the volunteerreported significant side effects (stomach irritation, nausea andheadache). Alternatively, the antidepressant in the above embodimentsused can be natural product or natural product extract instead ofsynthetic SSRI. Preferably the natural antidepressant is St. John's wortextract such as those commercially available as nutraceuticals andmedicines used for mood improvement. The preferred dosage of St. John'swort extract used is between 300 mg˜3000 mg. Preferably the St. John'swort extract contains at least 3% hypericin, adhyperforin,pseudohypericin, and hyperforin combined weight. In one embodiment, inrepeated experiments a volunteer took 1 capsule containing 1000 mg ofSt. John's wort extract and one capsule containing 1000 mg of curcuminand 5 mg of piperine. After 2 hours, the average pre ejaculation timewas 15 minutes compared with 5 minutes previously without the drug. Thevolunteer reported no side effects. In one embodiment, in repeatedexperiments a volunteer took 2 capsules each containing 1000 mg of St.John's wort extract and one capsule containing 1000 mg of curcumin and 5mg of piperine. After 2 hours, the average pre ejaculation time was 20minutes compared with 5 minutes previously without the drug. Thevolunteer reported no side effects. In one embodiment, in repeatedexperiments a volunteer took a mixture of powder containing 1000 mg ofSt. John's wort extract, 1000 mg of curcumin and 5 mg of piperine. After2 hours, the average pre ejaculation time was 20 minutes compared with 5minutes previously without the drug. The commercially available St.John's wort extract contains low amount of hypericin, pseudohypericin,and hyperforin, it can be further concentrated to contain higher amountof hypericin, pseudohypericin, and hyperforin to reduce the amount ofdrug used accordingly. Furthermore, Morinda officinalis (MedicinalIndianmulberry Root) extract (100 mg˜1000 mg) can also be added to theformulation.

The main active agents in St. John's wort extract are hypericin,adhyperforin, pseudohypericin and hyperforin which can be oxidizedreadily therefore show reduced potency. Curcuminoid is potentantioxidant which protect the active agents in St. John's wort extractfrom being oxidized therefore improve their potency when beingco-formulated and taken together. This is one of the mechanisms thatcurcuminoid plus St. John's wort extract shows better therapeuticalefficacy than using St. John's wort extract alone. Curcuminoid has lowbioavailability and most of them keep intact in gastrointestinal (GI)tract, therefore can protect the drug from being oxidized for a longertime in GI tract than other antioxidant that can be absorbed in GI tractreadily.

Curcuminoid can also be added to the formulation for other drugs toprotect them from being oxidized and increase their potency.

Among hypericin, pseudohypericin and hyperforin in St. John's wortextract, adhyperforin and hyperforin are most potent active substances.Preferably the composition in the current invention contains 5-100 mghyperforin or adhyperforin or their combination. Most preferably thecomposition in the current invention contains 10-50 mg hyperforin oradhyperforin or their combination. In one embodiment, in repeatedexperiments a volunteer took 1 capsule containing 10 mg of hyperforinfrom concentrated St. John's wort extract, 500 mg of curcumin and 5 mgof piperine. After 2 hours, the average pre ejaculation time was 10minutes compared with 5 minutes previously without the drug. Thevolunteer reported no side effects and reported better erection. Inanother embodiment, a volunteer took 1 capsule containing 10 mg ofhyperforin only and after 2 hours the average pre ejaculation time wasnot changed compared to the time previously without the drug. In anotherembodiment, in repeated experiments a volunteer took 1 capsulecontaining 20 mg of mixture of hyperforin and adhyperforin, and 500 mgof curcumin. After 2 hours, the average pre ejaculation time was 15minutes compared with 5 minutes previously without the drug. Thevolunteer reported no side effects. In another embodiment, in repeatedtests a volunteer took 1 capsule containing 30 mg of hyperforin only.After 2 hours, the average pre ejaculation time was slightly increasedto around 8 minutes compared with 5 minutes previously without the drug.However, headache was reported.

Alternatively, hyperforin in the above embodiments can be replaced withhyperforin derivatives/analogues such as those disclosed in U.S. Pat.No. 7,105,705 and U.S. Pat. No. 9,321,713. Hyperforinderivatives/analogues (e.g. orally taken 10˜100 mg) can also increasethe pre ejaculation time either used alone or in combination withcurcumin. The formulation containing both curcumin and hyperforinderivatives/analogues has better efficacy than using hyperforinderivatives/analogues alone.

Alternatively, Centella asiatica extract can be used alone or added toother embodiments in the current invention to increase the preejaculation time and treat depression. Centella asiatica extract'sactive component contains Centella triterpenic genine, Asiaticoside,Madecassoside, Asiatic & Madecassic acid. Preferably the composition inthe current invention as oral formulation contains 100-5000 mg Centellatriterpenic genine or Asiaticoside or Madecassoside or Asiatic orMadecassic acid or their combination. In another embodiment, a volunteertook 1 capsule containing 2000 mg of Centella triterpenic genine andafter 2 hours the average pre ejaculation time was 10 minutes comparedwith 5 minutes previously without the drug. In another embodiment, avolunteer took 2000 mg of Centella triterpenic genine, 30 mg hyperforinand 500 mg of curcumin, and after 2 hours the average pre ejaculationtime was 15 minutes compared with 5 minutes previously without the drug.

Alternatively, Tramadol can be used in all the above embodiments. WhenTramadol is used, antidepressant (e.g. synthetic SSRI or St. John's wortextract) can be omitted or the curcumin can be omitted from theformulation although the combination of all three is also effective. Theterm “tramadol” is used herein to refer to2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (“tramadol”)and all pharmaceutically-acceptable forms and derivatives of tramadol.In particular, the term includes the N-oxide derivative (“tramadolN-oxide”) and the O-desmethyl derivative (“O-desmethyl tramadol”). Theterm also includes the solvates, polymorphs, andpharmaceutically-acceptable acid addition salts of tramadol and itsderivatives. The term further includes all of the stereoisomers of anyof the foregoing, including individual stereoisomers (includingindividual enantiomers) and mixtures of stereoisomers (including theracemates). Preferred dosage is between 5 mg˜50 mg.

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 10 mg of paroxetine, 20 mg of Tramadol. After 3 hours, theaverage pre ejaculation time was 25 minutes compared with 5 minutespreviously without the drug. The volunteer reported slight side effects(mild nausea).

In another embodiment, in repeated experiments a volunteer took acapsule containing 3 mg of escitalopram, 20 mg of Tramadol. After 3hours, the average pre ejaculation time was 25 minutes compared with 5minutes previously without the drug. The volunteer reported no sideeffects. While 20 mg of Tramadol only increase the average preejaculation time to 10 min.

In another embodiment, in repeated experiments a volunteer took acapsule containing 500 mg of curcumin, 2 mg of piperine, 20 mg ofTramadol. After 3 hours, the average pre ejaculation time was 25 minutescompared with 5 minutes previously without the drug. The volunteerreported no side effects.

In one embodiment, in repeated experiments a volunteer took a capsulecontaining 500 mg of curcumin, 2 mg of escitalopram, 10 mg of Tramadol.After 3 hours, the average pre ejaculation time was 25 minutes comparedwith 5 minutes previously without the drug. The volunteer reported noside effects.

The current invention disclosed that curcuminoid can be co-formulatedtogether or be administered together with other drugs having ejaculationdelaying effect to further improve their ejaculation delaying effect,reduce drug dose and reduce side effect. Besides the drugs listed above,other drugs or agents having ejaculation delaying effect can also beused in combination with curcuminoid to boost their efficacy and reducetheir side effect and dose. Examples of these agents include but are notlimited to morphine and morphine derivatives (e.g. those disclosed inU.S. Pat. No. 8,158,764), Delta opioid receptor agonist (e.g. thosedisclosed in U.S. patent application Ser. No. 11/696,806) and certainserotonin agonists and antagonists (e.g. those disclosed in U.S. Pat.No. 6,037,360).

The current invention also provides method and formulations containingcurcumin and St. John's wort extract to treat depression. The preferreddosage of St. John's wort extract used is between 300 mg˜3000 mg. Thepreferred dosage of curcumin extract used is between 300 mg˜3000 mg. Apatient suffering depression took one capsule three times daily and eachcapsule contains St. John's wort extract 300 mg and curcumin 500 mg.After two weeks, the patient report much improved mood and no sideeffects were observed. Piperine 2-20 mg can also be added to theformulation. Morinda officinalis (Medicinal Indianmulberry Root) extract(100 mg˜1000 mg) can also be added to the formulation.

The current invention also provides method and formulations containingcurcumin and escitalopram to treat depression. The preferred dosage ofcurcumin used is between 300 mg˜3000 mg. The preferred dosage ofescitalopram used is between 5 mg˜10 mg. A patient suffering depressiontook one capsule daily and each capsule contains escitalopram 5 mg andcurcumin 500 mg. After two weeks, the patient report much improved moodcomparable to taking escitalopram 10 mg daily and no side effects wereobserved. Piperine 2-20 mg can also be added to the formulation.

The current invention also provides method and formulations containingescitalopram and St. John's wort extract to treat depression. Thepreferred dosage of St. John's wort extract used is between 300 mg˜3000mg. The preferred dosage of escitalopram used is between 5 mg˜10 mg. Apatient suffering depression two capsules daily and each capsulecontains St. John's wort extract 300 mg and escitalopram 5 mg. After oneweeks, the patient report much improved mood comparable to takingescitalopram 20 mg daily. Curcumin 200-500 mg and Piperine 2-20 mg canalso be added to each capsule. Furthermore, Morinda officinalis(Medicinal Indianmulberry Root) extract (100 mg˜1000 mg) can also beadded to the formulation.

In the above methods and formulations to treat depression, the SSRI canbe replaced with one synthetic SNRI such as venlafaxine and duloxetineor Valdoxan. The amount of SNRI or Valdoxan used in the formulation canbe lower than they being used alone. Normally half daily dose is enoughto reach the desired effect.

The current invention also provides formulations containing curcumin asinjection dosage to treat diseases such as cancer or Alzheimer. Itcontains curcumin solid lipid nanoparticles, which can be made by amicroemulsion technique such as using microfluidizer at suitabletemperature (e.g. at 25-75 degrees C.). It contains curcumin 0.1%-10%,lecithin (e.g. from soybean or egg) 0.2% -20%, optionally surfactant%1˜10%, carbohydate such as lactose, glucose, sugar 1%-20% and water andpH adjusting reagent such as PBS. The mixture can be further lyophilizedto improve long term storage stability. When injected to the patient, itprovides better bioavailability and better therapeutical effects.

The composition containing both curcumin and St. John's wort extract orcomposition containing both curcumin and hyperforin can be used forAlzheimer treatment. For example, a capsule containing 500 mg curcumin,Piperine 2 mg and 500 mg St. John's wort extract can be taken orally 3times a day to treat Alzheimer. In another example, a capsule containing500 mg curcumin and 30 mg tetrahydrohyperforin can be taken orally 2times a day to treat Alzheimer. In another example, a capsule containing500 mg curcumin and 30 mg hyperforin can be taken orally 2 times a dayto treat Alzheimer. They can be also be made in injection form to treatAlzheimer.

The current invention also provides a formulation containing curcuminand cordycepin to treat cancer or reduce the side effect ofradio/chemotherapy. Preferred curcumin amount is between 300 mg-3 g, andthe preferred amount of cordycepin is between 5-100 mg. The cordycepincan be in the form of Cordyceps sinensis extract, Cordyceps militarisextract or those from fermentation as well as synthetic cordycepin. Inone embodiment, the formulation is a capsule or tablet contains 500 mgof curcumin, 5 mg of piperine and 20 mg of synthetic cordycepin (or 500mg of Cordyceps militaris extract which contains 3% cordycepin). Apatient takes it three times a day for cancer treatment.

The current invention also provides a formulation containing curcuminand epimedium brevicornu (Horny Goat Weed) extract to treat erectiledysfunction. Preferred curcumin amount is between 300 mg-1 g, and thepreferred amount of Epimedium brevicornu extract is between 100 mg-1 g,which can be made from 3-20 g dry Epimedium brevicornu. In oneembodiment, the formulation is a capsule or tablet contains 500 mg ofcurcumin, 500 mg of Epimedium brevicornu extract standardized to contain10% icariin. Furthermore Maca Extract 75 mg -300 mg can also beincorporated to the formulation. A volunteer took one capsule 3 hoursbefore intercourse showed improved erection and slightly increasedejaculation latency. St. John's wort extract 300 mg˜1000 mg can also beadded to the capsule/tablet to further increase the ejaculation latencytime.

In all the above inventions, suitable curcumin type compound can beeither turmeric extract, curcumin (diferuloylmethane) or curcuminoid(e.g. that extracted from turmeric, contains approximately 70˜80%diferuloylmethane, 10-20% demethoxycurcumin, and 5-10%bisdemethoxycurcumin) or one or more selected from natural curcuminderivatives including curcumin metabolites includingtetrahydrocurcuminoids (e.g. curcumin glucuronide, curcumin sulfate,tetrahydrocurcumin, and hexahydrocurcumin) or synthetic curcuminderivatives such as curcumin mono or di glycoside, curcumin mono or dicarboxylic acid ester, curcumin mono or di phosphate. The curcumin(diferuloylmethane) and tetrahydrocurcumin performs similar ascurcuminoid extracted from turmeric. Curcumin can be in the form of oneor more curcuminoid/curcumin derivatives in complex with micelles,emulsion, nanoparticles, liposome and cyclodextrin such as alpha orbeta-cyclodextrin or hydroxypropyl-γ-cyclodextrin andhydroxypropyl-beta-cyclodextrin. Optionally it can further contains 1˜20mg of piperine or 1 mg-200 mg turmeric oil. The above natural productsbased formulations can be used as nutraceuticals without being approvedas drugs.

Rotundine (rotundine) is extracted from the plant StephaniaTetrahydropalmatine L-body, also known as Rotundine ortetrahydropalmatine, palmatine (e.g. L-tetrahydropalmatine, L-THP), ananalgesic. It can also be chemically synthesized. Rotundine can be usedalone or added to all the formulations in the current invention for PEin effective therapeutical amount (e.g. 10 mg˜200 mg) to increase theirpotency in increasing ejaculation latency. The combination of rotundinewith SSRIs (e.g. those used in the previous examples) can provide betterdelaying ejaculation effect than using them alone. Rotundine can causeuser feel sleepy. A medicine that can antagonize hypnotic effect (e.g.Caffeine 10 mg˜100 mg and/or Taurine 300 mg˜1000 mg) can be added to theformulation.

For example, rotundine can be co-formulated with antidepressant to treatdepression and increase ejaculation latency. Example of suitable amountof antidepressant used in the formulation is Paroxetine 2.5-30 mg,Sertraline 5-100 mg, escitalopram 1-20 mg, citalopram 2-40 mg,dapoxetine 5-60 mg, fluoxetine 5-80 mg, Venlafaxine 5-30 mg, duloxetine5-60 mg. Example of suitable amount of rotundine is between 10˜500 mg,preferably between 20˜200 mg; for example, 30 mg or 60 mg or 120 mg. Inone embodiment, a volunteer took a capsule containing 10 mg ofescitalopram, 50 mg of rotundine with optional 20-100 mg caffeine andoptional 100-500 mg taurine 1-2 hours before sex. In another embodiment,a volunteer took a capsule containing 10 mg of paroxetine, 30 mg ofrotundine and 10 mg of caffeine 2 hours before sex. In one embodiment, avolunteer took a capsule containing 5 mg of paroxetine, 500 mg ofcurcumin and 60 mg of rotundine 2 hrs before sex. In one embodiment, avolunteer took a capsule containing 5 mg of escitalopram, 500 mg ofcurcumin, 50 mg caffeine and 30 mg of rotundine 2 hrs before sex. In oneembodiment, a volunteer took a capsule containing 500 mg of curcumin and100 mg of rotundine 2 hrs before sex. In one embodiment, a volunteertook a capsule containing 5 mg of escitalopram, 500 mg of curcumin and30 mg of rotundine 1 or 2 hrs before sex. Using the above combinationsshowed better efficacy in increasing ejaculation latency than using SSRIalone or rotundine alone. Natural antidepressant such as St. John's wortextract or its active components such as hyperforin can also be used incombination with rotundine. In one embodiment, a volunteer took acapsule containing 10-50 mg of hyperforin and 30-90 mg of rotundine and30 mg caffeine with optional 500 mg taurine 1 or 2 hrs before sex toincrease ejaculation latency. The inventor discovered that usingrotundine alone (e.g. taken orally 50˜200 mg 1 hr before sex) can alsoincrease ejaculation latency, but using it in combination with SSRI orcurcumin increases its efficacy. PDES inhibitor drugs (e.g. sildenafil)can also be added to the oral formulations such as tablet or capsule.

Alternatively, Melatonin (e.g. 1˜20 mg) can also be used instead ofrotundine or be used together with above formulations.

Alternatively, Corydalis genus such as Rhizoma Corydalis (Corydalisyanhusuo) extract (e.g. 500˜10000 mg such as 5:1 extract usingwater/ethanol extraction) or Stephania rotunda extract can also be usedinstead of rotundine in the above embodiments to increase preejaculation time or to treat depression alone or in combination withcurcumin. The active ingredients of Rhizoma Corydalis extract containalkaloids including corydaline, dl-Tetrahydropalmatine, protopine,L-tetrahydropalmatine, dl-Tetrahydrocladus Alkaloids,L-tetrahydrocannabinol, beta-high-celandine, coptisine, corynebacterium,corydalis, berberine, Tetrahydropalmatine Tetrandrine, alkaloiddehydrocorybulbine (DHCB), alkaloids glaucine, palmatine, d-Corydaline,Tetrahydrocolumbamine, Corydalis H, Corydalis I, Corydalis J, CorydalisK, Corydalis L, α-Allocryptopine, Dehydrocorydaline, d-Corybulbine,Dehydrocorydalmine, Corydalmine, Corypalmine,N-methyltetrahydrocolumbamine, N-methyltetrahydrocoptisine andNorisocorydin. These compounds have similar effect and can be used aspurified form or their combination for the current invention. Othertetrahydroprotoberberines (THPB) such as levostepholidine, 1-scoulerineand D,L-govadine can also be used in the current invention. Preferablythe dosage of the compound listed above or their combination used forthe current invention is between 30 mg˜3000 mg.

In one embodiment, a volunteer took 5 capsules containing totally 1000mg of Rhizoma Corydalis extract (10:1 concentrate granule, equals to 50g bulk herb) with optional 20-100 mg caffeine and optional 100-500 mgtaurine 0.5-2 hrs before sex. In one embodiment, a volunteer took 2capsules containing totally 1000 mg of Rhizoma Corydalis extract (10:1concentrate granule, equals to 50 g bulk herb) and 20 mg caffeine 0.5-2hrs before sex. In one embodiment, a volunteer took 2 capsulescontaining totally 1000 mg of Rhizoma Corydalis extract (10:1concentrate granule, equals to 50 g bulk herb) and 500 mg St. John'swort extract 0.5-2 hrs before sex. In one embodiment, a volunteer took50 mL liquid formulation contains 100 mg of rotundine and 100 mgdehydrocorybulbine (DHCB) 2 hrs before sex. The capsules can containsadditional curcumin or the like as described previously. In oneembodiment, a volunteer took 2 capsules containing totally 1000 mg ofRhizoma Corydalis extract (10:1 concentrate granule, equals to 50 g bulkherb) and 500 mg St. John's wort extract and 500 mg curcumin withoptional 20-100 mg caffeine and optional 100-500 mg taurine 0.5-2 hrsbefore sex. In one embodiment, a volunteer took 50 mL liquid formulationcontains 100 mg of rotundine and 100 mg dehydrocorybulbine (DHCB) and 30mg of hyperforin and 30 mg adhyperforin 0.5-2 hrs before sex. In oneembodiment, a volunteer took a capsule containing 500 mg of curcumin and60 mg of rotundine and 60 mg dehydrocorybulbine (DHCB) and 60 mglevostepholidine 2 hrs before sex. All these formulation can causedelayed ejaculation. Extract from danshen root, Panax notoginseng, RadixAngelicae Dahuricae, Rhizoma Cyperi Rotundi, Rhizoma and LigusticiChuanxiong can also be added to the formulation (e.g. extract equals to25 g of bulk herb). The active compound from these extract (e.g. 500 mgcoumarin of angelicae dahuricae) can also be used instead of the crudeextract.

Furthermore, the above formulations can be added with dopamine receptorantagonist in effective therapeutical amount to increase their potencyin increasing ejaculation latency. The combination of dopamineantagonist with SSRIs can provide better delaying ejaculation effectthan using them alone. Examples of suitable dopamine antagonist includeChlorpromazine, Pimozide, Metoclopramide, Sulpiride, Haloperidol. Thedopamine antagonist can be dopamine D3 receptor antagonist such asBP897, CAM89, NGB2904, NGB2849, PG619, CJB090, YQA14, PG01037,RGH188/cariprazine, PG622, FAUC365, ST-198, SB-269652, SB-277011A,SB-414796, R-PG648, PG01037, ABT-925, SR21502, GSK598809, GSK618334,BAK2-66, Buspirone, S33084 and S33138. They can be given to the personin need as an oral formulation 0.5˜3 hrs before sex either alone or incombination with other ingredient such as SSRI, hyperforin, curcumin orrotundine as described previously in the current disclosure. The amountused in the formulation to delay ejaculation generally is less than theamount (e.g. 20%˜90) of that used in clinics for other indication usingdopamine antagonist. For example in one embodiment, a person in need cantake 50 mg GSK598809 or GSK618334 1-2 hrs before sex to delayejaculation; in another embodiment, a person in need can take 30 mgGSK598809 and 1000 mg 2 hrs before sex. In another example, a person inneed can take 30 mg GSK598809 and 100 mg L-tetrahydropalmatine 1 hrbefore sex. In another example, a person in need can take 30 mgGSK598809 and 100 mg L-tetrahydropalmatine and 30 mg caffeine 1 hrbefore sex. In another example, a person in need can take 30 mgGSK598809 and 10 mg escitalopram 1-2 hrs before sex. In another example,a person in need can take 30 mg GSK598809 and 500 mg curcumin 1-2 hrsbefore sex. In another example, a person in need can take 30 mgGSK598809 and 20 mg hyperforin 1-2 hrs before sex. In another example, aperson in need can take 5 mg Buspirone and 10 mg escitalopram 1-2 hrsbefore sex. In another embodiment, a person in need can take 3 mgCariprazine 1-2 hrs before sex to delay ejaculation; in anotherembodiment, a person in need can take 2 mg Cariprazine and 1000 mg 2 hrsbefore sex. In another example, a person in need can take 3 mgCariprazine and 100 mg L-tetrahydropalmatine 1 hr before sex. In anotherexample, a person in need can take 3 mg Cariprazine and 100 mgL-tetrahydropalmatine 1 hr before sex. In another example, a person inneed can take 3 mg Cariprazine and 10 mg escitalopram 1-2 hrs beforesex. In another example, a person in need can take 30 mg Cariprazine and500 mg curcumin 1-2 hrs before sex. In another example, a person in needcan take 3 mg Cariprazine and 20 mg hyperforin 1-2 hrs before sex.

Preferably the dosage form used for the current invention is an orallytaken formulation such as capsule, liquid capsule, tablet, lozenge,emulsion, solution and etc, which contains therapeutically effectiveamount of active ingredient and pharmaceutically acceptable excipientssuch as starch, cellulose, gelatin and etc, which is well known to theskilled in the art.

What is claimed is:
 1. A method of managing sexual dysfunction orimproving sexual control in a mammal in need of treatment comprisingadministering on an as-needed basis to the mammal a compositioncomprising tetrahydropalmatine and serotonin reuptake inhibitor in atherapeutically effective amount.
 2. The method of claim 1, wherein themammal is a human male.
 3. The method of claim 1, wherein the serotoninreuptake inhibitor is selected from a group consisting of St. John'sWort extract, hyperforin, paroxetine, sertraline, dapoxetine,escitalopram and citalopram.
 4. A method of managing sexual dysfunctionor improving sexual control in a mammal in need of treatment comprisingadministering on an as-needed basis to the mammal a compositioncomprising Corydalis Yanhusuo extract in a therapeutically effectiveamount.
 5. The method of claim 4, wherein the composition furthercomprise St. John's Wort extract.
 6. The method of claim 4, wherein thecomposition further comprise curcuminoid.
 7. A formulation for delayingejaculation comprising Corydalis extract or tetrahydropalmatine,curcuminoid and at least one agent selected from a group consisting ofparoxetine, sertraline, dapoxetine, Escitalopram, Citalopram and St.John's Wort extract.
 8. The formulation of claim 7 wherein thecurcuminoid is selected from a group consisting of curcumin,desmethoxycurcumin, bis-desmethoxycurcumin, tetrahydrocurcuminoid,curcumin glucuronide, curcumin sulfate, hexahydrocurcumin orcombinations thereof.
 9. The formulation of claim 7, wherein the St.John's Wort extract is rich in hyperforin.